The O22 trial's positive result for adjuvant Pembrolizumab plus Belzutafan was unexpected, as experts believed kidney cancer recurrence was primarily immune-driven, not HIF-driven. This outcome forces a re-evaluation of the underlying biology of recurrence and suggests a significant role for HIF inhibition in the adjuvant setting.
The PSMA Addition study, adding lutetium in metastatic hormone-sensitive prostate cancer, showed an RPFS benefit. However, initial data suggested adverse quality of life scores. Upcoming results on pain and skeletal events are critical to determine if the toxicity profile undermines its clinical utility in this earlier disease setting.
Despite Belzutafan's clinical successes, effective biomarkers for patient selection are almost non-existent. Experts anticipate a significant increase in understanding over the next 12-24 months from correlative studies, which will likely reveal novel gene expression and tissue-based markers beyond obvious candidates like serum EPO.
The O11 trial (Len-Belzutafan vs. Cabozantinib) presents the first randomized Phase 3 data for a VEGF/HIF inhibitor combination. Its results will be pivotal in determining if this more toxic doublet approach is justified over monotherapy for IO-refractory kidney cancer, weighing the magnitude of benefit against increased side effects.
Upcoming data for the HER2-ADC Disitamab Vedotin will test if its efficacy is enriched in HER2-high patients. This trial spotlights a key field-wide dilemma: is specific enrichment necessary, or does a "bystander effect," as seen in breast cancer, mean even low HER2 expression is enough, complicating patient selection and the drug's positioning.
Data from trials like Niagara suggests a powerful new paradigm for assessing treatment success. Combining urine tumor DNA (uTDNA) for local disease and circulating tumor DNA (ctDNA) for systemic relapse offers a more dynamic view than traditional pathology and is poised to become the superior surrogate endpoint in bladder cancer trials.
The B15 trial shows EV-Pembro is superior to chemotherapy in muscle-invasive bladder cancer. However, the true benchmark is now the Niagara study (chemo + durvalumab), which already beat chemo alone. The debate will focus on whether EV-Pembro offers a significant enough improvement to become the definitive standard over this new chemo-IO combination.